title: SNPs located at CpG sites modulate genome-epigenome interaction.
abstract: DNA methylation is an important molecular-level phenotype that links genotypes and complex disease traits. Previous studies have found local correlation between genetic variants and DNA methylation levels (cis-meQTLs). However, general mechanisms underlying cis-meQTLs are unclear. We conducted a cis-meQTL analysis of the Genetics of Lipid Lowering Drugs and Diet Network data (n = 593). We found that over 80% of genetic variants at CpG sites (meSNPs) are meQTL loci (P-value<10(-9)), and meSNPs account for over two thirds of the strongest meQTL signals (P-value<10(-200)). Beyond direct effects on the methylation of the meSNP site, the CpG-disrupting allele of meSNPs were associated with lowered methylation of CpG sites located within 45 bp. The effect of meSNPs extends to as far as 10 kb and can contribute to the observed meQTL signals in the surrounding region, likely through correlated methylation patterns and linkage disequilibrium. Therefore, meSNPs are behind a large portion of observed meQTL signals and play a crucial role in the biological process linking genetic variation to epigenetic changes.
authors.affiliation: Department of Biostatistics; University of Alabama; Birmingham, AL USA.
authors.forename: Degui
authors.initials: D
authors.lastname: Zhi
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.forename: Steven A
authors.initials: SA
authors.lastname: Claas
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: Devin M
authors.initials: DM
authors.lastname: Absher
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015894:Genome, Human; D006801:Humans; D020641:Polymorphism, Single Nucleotide
keywords: DNA methylation; Infinium Human Methylation 450K BeadChip; epigenome-wide study; meQTL; meSNP